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Inhibition of human IAPP fibril formation does not prevent -cell death: evidence for distinct actions of oligomers and fibrils of human IAPP

¹Larry Hillblom Islet Research Center, University of California Los Angeles David Geffen School of Medicine, Los Angeles; ²Department of Molecular Biology and Biochemistry, University of California, Irvine; and ³Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California

Submitted 17 February 2006 ; accepted in final form 17 July 2006

Type 2 diabetes mellitus (T2DM) is characterized by an 60% deficit in -cell mass, increased -cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce -cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect -cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced -cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108–127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642–1644, 2003), and does not protect -cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate -cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.

islet amyloid polypeptide; human islet amyloid polypeptide; rifampicin

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